Enantioselective Synthesis of γ-Carboxy-β-amino Acids by Desymmetric Alcoholysis of 3-Aminoglutaric Anhydrides = 3-아미노글루타르산 무수물의 비대칭 알코올 분해를 통한 γ-카복시-β-아미노산의 입체선택적 합성

다국어 초록 (Multilingual Abstract)

β-Amino acids are structural units found in various natural products and bioactive compounds. Due to their ability to provide metabolic stability and modulate drug properties, they have gained attention as promising molecular scaffolds in pharmaceutical research. In response, many studies on synthesis of β-amino acids have been reported. However, most involve expensive catalysts or face challenges from the complex design and synthesis of required precursors, limiting their practicality. Therefore, in this study, we propose a synthetic strategy using desymmetric alcoholysis with cinchona-derived bifunctional catalysts as an efficient and environmentally friendly approach for the enantioselective synthesis of β-amino acid derivatives.
Desymmetric alcoholysis is a desymmetrization strategy involving the selective ring-opening of a cyclic anhydride by an alcohol under catalytic conditions to form a chiral center. It is a representative method for synthesizing chiral products from symmetric substrates. Since the first report on the desymmetric alcoholysis of glutaric anhydrides in the 1980s, many studies have focused on substrates with alkyl or aryl substituents at the C3 position, where the chiral center forms. However, no examples have been reported using an amine substituent to obtain chiral amine compounds. Inspired by this, we designed a strategy to synthesize compounds bearing a chiral amine at the C3 position and developed a new method for the enantioselective synthesis of γ-carboxy-β-amino acid derivatives.
After C3-amination of glutaric anhydride, a suitable protecting group was installed to enable the catalytic reaction. First, a benzoyl group was introduced to convert the amine into an amide, which modulated its nucleophilicity and enhanced chemical stability under catalytic conditions as well as during various derivatizations. Based on ¹H-NMR titration experiments that predicted a hydrogen bonding model between the catalyst and substrate, a trifluoroacetyl (TFA) group was introduced to the amide to promote effective interactions and thereby improve enantioselectivity.
Using the synthesized cyclic aminoglutaric anhydride as a substrate, various cinchona-derived catalysts were screened, with the highest enantioselectivity observed using a dimeric cinchona-based squaramide catalyst. Reaction conditions such as temperature and concentration were optimized, affording a 95% yield and 94% ee. To expand the substrate scope of the catalytic reaction, benzoyl derivatives with diverse substituents and other protecting groups such as benzyloxycarbonyl (Cbz) and phthalimide were employed. These catalytic reactions achieved enantioselectivities up to 98% ee.
Density Functional Theory (DFT) calculations were performed based on the stereochemical structures of reactants and the absolute configurations of the major products. From these, the reaction complex comprising the catalyst, substrate, and nucleophile was predicted, allowing the proposal of a plausible mechanism for the desymmetric alcoholysis.
The γ-carboxy-β-amino acid derivatives obtained from the asymmetric reaction were further transformed into various chiral amines via functional group modifications. Selective reduction of the ester and carboxylic acid groups yielded enantiomeric alcohol and δ-lactone derivatives with retention of stereochemistry. Through sequential transformations, the carboxylic acid was converted into a primary amine. Additionally, acidic heating successfully removed the benzoyl group, yielding the free β-amino acid.

국문 초록 (Abstract)

β-아미노산은 다양한 천연물과 생리활성 물질에 포함된 구조로, 대사적 안정성을 제공하고 약물의 성질을 조절할 수 있다는 특징으로 인해 제약 연구에서 유망한 분자 골격으로 주목받고 있다. 이러한 수요에 따라 β-아미노산의 합성을 위한 다양한 연구들이 보고되었으나, 대부분 값비싼 촉매를 사용하고, 반응에 필요한 전구체의 복잡한 설계 및 합성에 어려움이 따르는 등의 여러 한계점이 존재한다. 이에 본 연구에서는 β-아미노산 유도체를 입체선택적으로 합성하는 효율적이고 친환경적인 방법으로, 신코나 유래 이중기능성 촉매를 이용한 비대칭 알코올 분해 반응이라는 합성 전략을 제안하였다.
비대칭 알코올 분해 반응은, 촉매 조건하에서 알코올이 고리형 산 무수물을 선택적으로 개환하며 카이랄 중심을 형성하는 반응으로, 대칭적인 기질로부터 카이랄 생성물을 합성하는 대표적인 비대칭화 전략 중 하나이다. 1980년대 글루타르산 무수물의 비대칭 알코올 분해 반응이 처음 보고된 이래, 카이랄 중심을 형성하는 3번 탄소 위치에 알킬 또는 아릴 치환기를 갖는 기질들에 대한 다양한 연구들이 수행되었지만, 아민 치환기를 도입하여 카이랄 아민 화합물을 합성한 사례는 보고되지 않았다. 이에 착안하여, 3번 탄소에 카이랄 아민을 도입한 화합물 합성 전략을 설계하였고, 이를 통해 β-아미노산 구조의 생성물, γ-카복시-β-아미노산 유도체를 입체선택적으로 합성하는 새로운 방법을 개발하였다.
글루타르산 무수물의 3번 탄소에 아민을 합성한 후, 촉매 반응을 위해 아민에 적절한 보호기를 도입하였다. 먼저, 아민의 친핵성을 조절하고, 촉매 반응 조건 및 다양한 유도체화 반응에 대한 화학적 안정성을 확보하기 위해 벤조일기를 도입하여 아마이드 구조로 변환하였다. 이후, 수소 NMR 적정 실험을 통해 촉매와 기질 간의 수소결합 모델을 예측한 결과를 바탕으로, 기질과 촉매의 효과적인 상호작용을 유도하고 입체선택성을 향상시키기 위해 아마이드에 트라이플루오로아세틸(TFA)기를 추가로 도입하였다.
합성한 고리형 아미노글루타르산 무수물을 기질로 하여 다양한 신코나 유래 촉매들을 적용해본 결과, 이합체 구조의 신코나 유래 스퀘어아마이드 촉매에서 가장 높은 입체선택성이 관찰되었다. 반응 온도와 농도 등의 조건을 세부적으로 조절하였고, 최적화된 반응 조건에서 95%의 수율과 94% ee의 입체선택성을 확보하였다. 또한, 비대칭 촉매 반응의 적용 범위를 확대하기 위하여 다양한 치환기를 갖는 벤조일 유도체와 함께, 벤질록시카보닐(Cbz), 프탈리마이드 등을 도입하여 촉매 반응을 수행하였고, 최대 98% ee의 높은 입체선택성을 기록하였다.
반응물들의 입체 구조와 주생성물의 절대 배열을 바탕으로 DFT 계산을 수행하였고, 이를 통해 촉매, 기질, 그리고 친핵체로 구성된 반응 복합체를 예측하여 비대칭 촉매 반응의 메커니즘을 제시하였다.
비대칭 촉매 반응 생성물 γ-카복시-β-아미노산 유도체는 다양한 작용기 변환을 통해 여러 카이랄 아민 화합물로 확장이 가능하였다. 에스터와 카복시산의 선택적 환원을 통해 화합물의 입체선택성을 유지하면서 각각 거울상 이성질체 관계에 있는 알코올과 δ-락톤 구조의 화합물을 합성하였다. 일련의 화학 반응을 통해 카복실산을 1차 아민으로 변환하였고, 산 조건에서 가열함으로써 벤조일기가 제거된 자유 형태의 β-아미노산을 성공적으로 합성하였다.

목차 (Table of Contents)

• ABSTRACT i
• TABLE OF CONTENTS iii
• LIST OF FIGURES vii
• LIST OF TABLES viii
• LIST OF SCHEMES ix
• INTRODUCTION 1
• 1 Cinchona-derived bifunctional organocatalysts 1
• 1.1 Introduction of asymmetric organocatalysis 1
• 1.2 Bifunctional organocatalysts 2
• 1.3 Cinchona-alkaloid for asymmetric catalysis 4
• 1.3.1 Asymmetric reactions by cinchona-derived catalysts 4
• 1.3.2 Structural character of cinchona alkaloids 5
• 1.4 Derivatization of cinchona-derived organocatalyst 6
• 1.4.1 Cinchona-derived thiourea organocatalysts 7
• 1.4.2 Cinchona-derived squaramide organocatalysts 8
• 1.4.3 Cinchona-derived dimeric organocatalysts 10
• 2 Asymmetric synthesis of β-amino acids 13
• 2.1 β-Amino acids in pharmaceutical research 13
• 2.2 β-Amino acids in natural products 14
• 2.3 Conventional synthetic methods of β-amino acids 15
• 2.3.1 Arndt-Eistert homologation of α-amino acids 15
• 2.3.2 Asymmetric hydrogenations 16
• 2.3.2.1 Metal-catalyzed asymmetric hydrogenations 16
• 2.3.2.2 Organocatalyzed asymmetric hydrogenations 17
• 2.3.3 Mannich-type reactions 17
• 2.3.4 Conjugate additions 19
• 2.3.4.1 Synthesis of chiral β3-amino acids 19
• 2.3.4.2 Synthesis of chiral β2-amino acids 20
• 3 Desymmetrization of dicarboxylic acid derivatives 22
• 3.1 Introduction of desymmetrization 22
• 3.2 Desymmetrization of cyclic anhydrides 23
• 3.2.1 Desymmetrization by oxygen nucleophiles 23
• 3.2.1.1 Alcoholysis of cyclic anhydrides with Lewis acids 23
• 3.2.1.2 Alcoholysis of cyclic anhydrides with Lewis bases 24
• 3.2.1.3 Enzymatic alcoholysis of cyclic anhydrides 29
• 3.2.2 Desymmetrization by sulfur nucleophiles 30
• 3.2.3 Desymmetrization by carbon nucleophiles 31
• 3.2.3.1 Grignard reagents 31
• 3.2.3.2 Metal-catalyzed nucleophilic substitutions 32
• 3.3 Desymmetrization of dialkyl esters 33
• 3.4 Desymmetrization of bicyclic bislactones 35
• 3.5 Desymmetrization of aminoglutarate derivatives 36
• 3.5.1 Enzymatic desymmetrization of dimethyl 3-aminoglutarate 36
• 3.5.2 Desymmetrization using chiral amines 36
• 3.6 Desymmetric alcoholysis of aminoglutaric anhydrides 37
• 3.6.1 Lack of desymmetrization for C3-aminated anhydrides 37
• 3.6.2 Design rationale for 3-aminoglutaric anhydrides 38
• 3.6.3 Synthetic utility of γ-carboxy-β-amino acids 39
• RESULTS AND DISCUSSION 41
• 1 Preparation of 3-aminoglutaric anhydrides 41
• 1.1 Preparation of benzamide as substrate 41
• 1.2 Preliminary catalytic experiment 41
• 1.3 Improvement of catalytic selectivity 42
• 1.3.1 Consideration about low selectivity 42
• 1.3.2 1H-NMR titration experiment of substrate with catalysts 43
• 1.3.3 Design of substrate for chiral induction 45
• 1.3.3.1 Trifluoroacetylation of amide group 45
• 1.3.3.2 Comparison of catalytic selectivity 46
• 2 Optimization of reaction conditions 46
• 2.1 Organocatalyst screening 46
• 2.2 Optimization of alcohol nucleophile 48
• 2.3 Optimization of catalytic conditions 49
• 2.3.1 Optimization of catalytic amount 49
• 2.3.2 Solvent screening 50
• 2.3.3 Optimization of concentration, temperature and equivalent 51
• 2.3.4 Optimization of alcohol equivalents at low temperature 52
• 2.4 Substrate scope of desymmetrization 53
• 2.4.1 Preparation of substrates 53
• 2.4.2 Substituted with electron-donating groups 54
• 2.4.3 Substituted with electron-withdrawing groups 55
• 2.4.4 Substituted with general protecting group of amine 56
• 2.4.5 Planned directions for further research 57
• 3 Plausible mechanism of desymmetric alcoholysis 58
• 3.1 Confirmation of absolute configuration 58
• 3.2 Density functional theory 59
• 3.3 Plausible catalytic mechanism 60
• 4 Derivatization of γ-carboxy-β-amino acids 62
• 4.1 Synthesis of β-amino-δ-lactones 62
• 4.2 Synthesis of debenzoylated δ-hydroxy-β-amino acids 63
• 4.3 Synthesis of β, γ-diamino acids 63
• CONCLUSION 65
• EXPERIMENTAL SECTION 66
• 1 General information 66
• 2 Preparation of cyclic anhydrides 67
• 2.1 Synthesis of dimethyl 3-aminoglutarate 67
• 2.2 Synthesis of N-protected dimethyl 3-aminoglutarates 68
• 2.3 Synthesis of cyclic anhydrides 76
• 3 Enantioselective desymmetric alcoholysis 86
• 4 Confirmation of absoulte comfiguration 99
• 5 Derivatization of γ-carboxy-β-amino acids 100
• 5.1 Synthesis of β-amino-δ-lactones 100
• 5.2 Synthesis of debenzoylated δ-hydroxy-β-amino acids 103
• 5.3 Synthesis of β, γ-diamino acids 104
• 6 1H-NMR titration experiment 107
• 7 X-ray crystallographic data 111
• 8 Computational method 114
• REFERENCES 117
• APPENDIX 124
• 국문초록 214
• ACKNOWLEDGEMENT 216